This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this study we address the Grand Challenge #6 of the Global Health Initiative: Learn which immunological responses provide protective immunity (against HIV-1). This past year we confirmed that, similar to primarily monophyletic transmission of HIV observed in Zambian couples where subtype C predominates, transmission in Rwanda where subtype A prevails is also largely monophyletic (90% overall rate). In contrast, multiple genetic variants were transmitted to 3/7 of subjects who were infected by a non-spouse. This multivalent transmission was statistically linked with the presence of inflammatory genital infections that might perturb the genital mucosa. In order to characterize immune response we isolated a B-cell hybridoma from a subtype C patient that produced a highly strain-specific neutralizing monoclonal antibody (Mab). Although derived from blood cells collected 4 years post infection, Mab 6.4C only neutralized viruses harboring autologous Env isolated during acute infection and for 2 months post infection, suggesting subsequent mutation-induced escape in Envs. We are now amplifying and sequencing near-full-length viral genomes from 40 Rwandan donors and their newly infected partners to examine genetic changes in virus that occur over time that explain escape from both neutralizing antibodies and from cytotoxic CD8+ T cell responses.